Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

Dong, Jun; Wu, Zeyu; Wang, Dan; Pascal, Laura E.; Nelson, Joel B.; Wipf, Peter; Wang, Zhou

doi:10.1158/1535-7163.mct-18-0432

Cited by 49Prostate Cancer Treatment and ResearchHeat shock proteins researchSperm and Testicular Function

Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

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Dong, Jun, Wu, Zeyu, Wang, Dan, Pascal, Laura E., Nelson, Joel B., Wipf, Peter, Wang, Zhou·2019·Molecular Cancer Therapeutics

DOI 10.1158/1535-7163.mct-18-0432PMC PMC6318070

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Abstract

The androgen receptor (AR) is a key driver and therapeutic target in androgen-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), and CRPC resistant to abiraterone and enzalutamide, two second-generation inhibitors of AR signaling. Because current AR inhibitors target a functioning C-terminal ligand-binding domain (LBD), the identification and characterization of cofactors interacting with the N-terminal domain (NTD) of AR may lead to new approaches to target AR signaling in CRPC. Using a pull-down approach coupled with proteomics, we have identified Hsp70 as a cofactor for the NTD of AR in prostate cancer cells. Hsp70 inhibition using siRNA or small molecules indicated that Hsp70 played an important role in the expression and transactivation of endogenous AR. Prostate-specific antigen (PSA) promoter/enhancer-driven luciferase assays showed that Hsp70 was also required for transactivation of AR mutant lacking LBD. Furthermore, clonogenic assays showed that an Hsp70 inhibitor, either alone or in synergy with enzalutamide, can inhibit the proliferation of 22Rv1, a widely used enzalutamide-resistant CRPC prostate cancer cell line. These findings suggest that Hsp70 is a potential therapeutic target for the treatment of enzalutamide-resistant CRPC.

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Huryn, D. M., Brodsky, J. L., Brummond, K. M., Chambers, P. G., Eyer, B. R., Ireland, A. W., Kawasumi, M., LaPorte, M. G., Lloyd, K. R., Manteau, B., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015251108 · Cited by 72 · cited 1× · see citing works
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MethodSelf-citation
A Short-activating RNA Oligonucleotide Targeting the Islet β-cell Transcriptional Factor MafA in CD34+ Cells
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BackgroundMethod
17α-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
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“A recent study reported the effect of Hsp70 regulation of the AR promoter through the activation and nuclear translocation of YB-1 (61).”
BackgroundMethod
Tanespimycin as Antitumor Therapy
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“B, C4-2 cells were transfected with expression vectors for GFP-tagged NTD, AR(1-293), and AR(294-556), along”
Method
Hsp70 Cochaperones HspBP1 and BAG-1M Differentially Regulate Steroid Hormone Receptor Function
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“Hsp70 was reported to also influence the LBD (60); however, we did not detect their interactions via co-IP in this study.”
Background
Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members
Manos-Turvey, A., Al-Ashtal, H. A., Needham, P. G., Hartline, C., Prichard, M., Wipf, P., & Brodsky, J. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.08.080 · Cited by 24 · cited 1×
“B, C4-2 cells were transfected with expression vectors for GFP-tagged NTD, AR(1-293), and AR(294-556), along”
MethodSelf-citation
FOXA1 modulates EAF2 regulation of AR transcriptional activity, cell proliferation and migration in prostate cancer cells
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Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer
Johnson, J. K., Skoda, E. M., Zhou, J., Parrinello, E., Wang, D., O’Malley, K. J., Eyer, B. R., Kazancioğlu, M. Z., Eisermann, K., Johnston, P. A., et al. (2016) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.6b00186 · Cited by 23 · cited 3× · see citing works
“the PSA-luciferase plasmid and Renilla plasmid (47) were treated with either VER-155008 or another Hsp70 inhibitor, 18BBQU (UPCMLD18BBQU015254),”
MethodSelf-citation
The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells
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“B, C4-2 cells were transfected with expression vectors for GFP-tagged NTD, AR(1-293), and AR(294-556), along”
BackgroundMethodSelf-citation
Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model
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BackgroundMethod
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Abstract 4022: Integrin β1 regulates doxorubicin resistance in breast cancer via FAK-mediated activation of ERK1 pathway
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MethodSelf-citation
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“GFP; (3) at least two peptides were identified.”
Background

Flagged first, then by citations

5 of the 74 references couldn’t be matched to a known paper.

Sorted by citations

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities
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Background
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Influential
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Authors: Dong, J., Wu, Z., Wang, D., Pascal, L. E., Nelson, J. B., Wipf, P., & Wang, Z.
Affiliations: University of Pittsburgh (US)
Central South University (CN)
Corresponding author: Wang, Zhou
ORCID: Dong, Jun
Wu, Zeyu
Pascal, Laura E.
Wipf, Peter
Wang, Zhou
Venue: Molecular Cancer Therapeutics
Publisher: American Association for Cancer Research (AACR)
Published: 2019-01-01
Volume: 18
Issue: 1
Pages: 39-50
ISSN: 1535-7163 (ISSN-L)
1538-8514
DOI: 10.1158/1535-7163.mct-18-0432
PMC: PMC6318070
OpenAlex: W2896349409
Cited by: 49
References: 74
Citations by year: 2026: 5 · 2025: 6 · 2024: 3 · 2023: 14 · 2022: 8 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 1
FWCI: 2.45
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Cancer Therapeutics (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIH (R01 CA186780, 1P50 CA180995, R50 CA211242)
CPF (P30 CA047904)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords: HSP70, androgen receptor, N-terminal domain, castration-resistant prostate cancer, enzalutamide resistance, abiraterone resistance, protein-protein interaction, transcriptional activation, prostate-specific antigen promoter, Hsp70 inhibitors, therapeutic target, 22Rv1 cells
MeSH terms: Benzamides, Binding Sites, Drug Synergism, Humans, Male, Nitriles, Phenylthiohydantoin, Protein Binding, Receptors, Androgen, Down-Regulation, Gene Expression Regulation, Neoplastic, Benzoquinones, HSP70 Heat-Shock Proteins, Drug Resistance, Neoplasm, Proteomics, Cell Line, Tumor, Lactams, Macrocyclic, Prostatic Neoplasms, Castration-Resistant

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Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

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